In this SPOTRIAS application, we propose 3 new studies, one of which (project #1) is a collaborative multicenter phase 2 trial across several SPOTRIAS centers, one entirely new project (project # 2), and one (project #3) which is the next phase of a project started during the first 5 years of our SPOTRIAS program. All three of these projects are translational in the true sense of the word. Project 1 is a trial of a combination of neuroprotective treatments (caffeinol and hypothermia), one of which (caffeinol) was discovered in our lab and has undergone extensive preclinical testing in our animal stroke models. The combination was also first tested in our lab. The phase 1 and early phase 2 evaluations of these treatments were part of the first SPOTRIAS from UT and UC San Diego, and showed feasibility and safety. In the spirit of translation, the study that we jointly propose in Project 1 is designed to replicate as much as possible the laboratory experiments which demonstrated the most robust benefit of this combination. The purpose of this study is to do a factorial design phase 2 study of both treatments alone and in combination compared with standard treatment in order to determine as quickly as possible which treatment arms should move forward to a phase 3 study. Project 2 is a study of a PPARgamma agonist in patients with ICH. Our lab was the first to demonstrate changes in PPARgamma expression in an animal model of ICH, and the PI of Project 2 was part of the lab team that first discovered that PPAR gamma agonists promoted the phagocytosis of the red blood cells comprising the hematoma. Project 2 is a direct clinical translation of that work. Finally, project 3 carries on our previous work with ultrasound enhanced clot lysis. The safety and benefit of ultrasound has been tested in our animal stroke models and in other labs, and then in a phase 2 study as part of our previous SPOTRIAS. In an effort to make this treatment more widely applicable, we have developed a hands-free ultrasound unit that we first tested in animals as part of a supplementary award to our first SPOTRIAS, and now propose to test for the first time in humans. We also propose 3 Cores (Clinical, Data, and Tissue) to support these translational studies, and a Career Development Program to train new investigators to carry out future translational studies. All of these projects and Cores were approved by the previous review of our grant, but there were concerns [unreadable] about the Data Core and Project #1 that we have thoroughly addressed in this re-submission. [unreadable] [unreadable] [unreadable]